A common feature in all dementias associated with Lewy Bodies is the accumulation and aggregation of the small 14kD protein a-synuclein in the perikaryon and proximal neurites. This proximal accumulation of ct- synuclein in diseased states is very different from the physiologic situation, where the protein is predominantly localized to distant presynaptic sites. Thus pathologic conditions lead to a mis-localization of a-synuclein into proximal neuronal compartments, in addition to the accumulation/aggregation of the protein. While many previous studies have focused on the biochemical processes leading to the aggregation of o> synuclein into the insoluble fibrils that are seen in the end-stage Lewy bodies, much less is known about the initial mechanisms that lead to the proximal mis-localization of the protein. As a-synuclein is synthesized in the neuronal perikarya and is transported into axons, eventually targeting to synapses, our working hypothesis is that defects in the mechanisms of axonal transport and/or presynaptic targeting of a-synuclein is the basis for its mis-localization in pathologic states. To test this hypothesis, we have developed novel model-systems and imaging tools that allow us to directly visualize and precisely quantify axonal transport and presynaptic targeting of a-synuclein in axons and boutons of living neurons. Indeed defects in transport/targeting of pathologic forms of a-synuclein are seen in this system, supporting our hypothesis. Completion of the proposed project will provide insights into initial pathologic mechanisms in these dementias, and may also lead to novel early therapeutic targets. RELEVANCE (See instructions): Dementias associated with Lewy bodies is a common cause of dementia among the elderly, second only to Alzheimer's. To date, there is no known cure. Our best chance of treating this disease is to attack it at an early stage, however, early mechanisms leading to these dementias is poorly understood. In this project we will unravel such early events by determining how a key protein gets misplaced in neurons, causing disease.